The current study tested the utility of the Implicit Relational Assessment Procedure (IRAP) as an analogue cognitive defusion intervention to alter implicit attitudes toward Abraham Lincoln and Adolf Hitler. One-hundred and twelve participants were randomly assigned to either a control or defusion condition. Participants first completed a series of self-report measures assessing psychological functioning and distress, as well as attitudes toward Lincoln and Hitler. Control condition participants then completed three IRAPs measuring implicit attitudes toward Hitler and Lincoln (H/L IRAP). Defusion conditions participants completed a pre-intervention H/L IRAP, received a rationale for defusion before completing a defusion IRAP, and then completed a post-intervention H/L IRAP. All participants finished the study by completing a second set of self-report measures. Results of the study indicated that when taking into account participant knowledge of defusion there were significant differences in IRAP performance post-intervention between conditions, although there were no significant differences in performance pre- to post-intervention within the defusion condition. Additionally, there were no differences between conditions on self-report measures at either time point, suggesting the IRAP was sensitive to changes in participant attitudes that self-reports were unable to detect. Thus, the results of this study indicate that the IRAP is a viable analogue defusion intervention, and future research should look to expand the defusion effect produced by the IRAP.

The current study tested the effects of a cognitive defusion intervention on implicit attitudes toward milk and lemon as measured by the Implicit Relational Assessment Procedure (IRAP). One-hundred and eleven participants were randomly assigned to one of four conditions: control math, control defusion, half defusion, or full defusion. Participants filled out a series of self-report measures at the beginning of the study on psychological functioning, as well as attitudes toward milk and lemon. Participants then completed a task specific to their condition, with control math participants completing a simple math task while defusion conditions completed a defusion intervention – word repetition technique (WRT) – for certain words. The control defusion condition completed the WRT for the words “car” and “rabbit,” the half defusion condition completed the WRT for the word “milk,” and the full defusion condition completed the WRT for the words “milk” and “lemon.” After completing the condition specific tasks, all participants completed a milk/lemon IRAP that included the words “milk” and “lemon” and pictures of milk and lemon. All participants finished the study by completing a final set of self-report measures. Results of the study indicated that IRAP performance was not significantly different between conditions following various levels of a defusion intervention. However, results showed that the pattern of IRAP response latencies did significantly vary between conditions, but this effect was driven by a significant difference on a single response latency between two conditions suggesting this finding is an artifact. Thus, the current study cannot conclude that a defusion intervention can significantly affect implicit attitudes towards common objects, and any future research should consider applying a defusion intervention to clinically relevant stimuli to further assess for defusion effects in the IRAP.

research examines associations between perfectionism and acceptance for the self and towards others, alongside their link with psychological health. Reported beliefs are compared with underlying implicit beliefs, as measured by response latencies on the Implicit Relational Assessment Procedure (IRAP; Barnes-Holmes et al., 2006). Ninetynine native English-language speaking university students completed measures of selforiented and other-oriented perfectionism, unconditional self-acceptance, acceptance of others and general health; together with the IRAP computer task. Self-perfectionism scores were observed to be significantly higher than other-perfectionism scores on both explicit and implicit measures. Acceptance of others was significantly higher than selfacceptance on explicit measures; however the two were non-significantly different as recorded by the IRAP. This suggests that participants may have under-reported selfacceptance levels or over-reported their acceptance of others. Possible reasons for this are explored. In addition, all explicit measures demonstrated no significant associations with implicit findings; meaning that participants‟ responses to the assessment tasks appeared to be driven by different processes. Low levels of explicit self-acceptance were the biggest predictor of psychological distress. As such, this research provides further support for the move towards acceptance-based strategies in the treatment of clinical perfectionism.

No description available.

Computational methods have become an integral part of drug development and can help bring new and better drugs to the market faster. The process of predicting the biological activity of large compound collections is known as virtual screening, and has been instrumental in the development of several drugs today in the market. Computational methods can also be used to elucidate the energies associated with chemical reactivity and predict how to improve a synthetic protocol. These two applications of computational medicinal chemistry is the focus of this thesis. In the first part of this work, quantum mechanics has been used to probe the energy surface of palladium(II)-catalyzed decarboxylative reactions in order to gain a better understating of these systems (paper I-III). These studies have mapped the reaction pathways and been able to make accurate predictions that were verified experimentally. The other focus of this work has been to develop virtual screening methodology. Our first study in the area (paper IV) investigated if the results from several virtual screening methods could be combined using data fusion techniques in order to get a more consistent result and better performance. The study showed that the results obtained from data fusion were more consistent than the results from any single method. The data fusion methods also for several target had a better performance than any of the included single methods. Next, we developed a dataset suitable for evaluating the performance of virtual screening methods when applied to large compound collection as a replacement or complement for high throughput screening (paper V). This is the first benchmark dataset of its kind. Finally, a method for using computationally derived reaction coordinates as basis for virtual screening was developed. The aim was to find inhibitors that resemble key steps in the mechanism (paper VI). This initial proof of concept study managed to locate several known and one previously not reported reaction mimetics against insulin regulated amino peptidase.

A doença articular, especificamente a osteoartrite é uma das enfermidades mais prevalentes e mais debilitantes que acomete os cavalos, tendo um grande impacto econômico na indústria eqüina. Assim sendo, a investigação contínua e avanços na área terapêutica são de fundamental importância. A osteoartrite é uma doença degenerativa que pode ser deflagrada por uma série de fatores e onde, ultimamente, todos os tecidos articulares encontram-se comprometidos. Não obstante, é na degradação da matriz extracelular da cartilagem articular que ocorrem os eventos de maior expressão e repercussão. Na gênese da degradação da matriz extracelular encontra-se um desequilíbrio entre os processos anabólicos e catabólicos responsáveis pela homeostase normal da cartilagem articular e pela adaptação deste tecido às forças que sobre ele incidem. Estes processos são orquestrados por proteínas anabólicas, como, por exemplo o fator de crescimento tipo insulina 1 (IGF-l), e por citocinas inflamatórias que, de forma contrária, são responsáveis pela depleção de colágeno e de proteoglicanas da matriz, representando o grupo de proteínas catabólicas, cujo exemplo clássico é a interleucina-1. A interleucina-1 tem papel central nos processos fisiopatológicos da osteoartrite por desencadear vários eventos catabólicos nos sinoviócitos e condrócitos, incluindo a indução de gens de metaloproteinases e agrecanases e de outros mediadores inflamatórios como a cicloxigenase, a prostaglandina E2 e as espécies reativas do oxigênio. Seus efeitos biológicos se verificam após a ligação com dois tipos de receptores específicos e são modulados pela ocorrência natural de uma proteína antagonista destes receptores. O presente estudo procurou observar os efeitos antiinflamatórios desta proteína antagonista do receptor (IRAP) no líquido sinovial de equino através do emprego da técnica de citometria de fluxo. Nos ensaios observou-se que: 1-a adição de IRAP às células de líquido sinovial estimuladas in vitro por LPS e PMA reduziu a liberação de espécies reativas de oxigênio produzidas por elas; 2 - o plasma, quando utilizado como controle, exibiu efeitos semelhantes aos do IRAP sobre as células de líquido sinovial ativadas in vitro; 3- o efeito antiinflamatório deve-se mais à variação na intensidade de produção de espécies reativas do oxigênio do que à flutuação no percentil de células do líquido sinovial engajadas em sua geração, in vitro. Estes resultados suportam a aplicabilidade terapêutica do IRAP® pelo efeito antiinflamatório verificado sobre as células do liquido sinovial avaliadas por citometria de fluxo. Eles corroboram, ainda, para o uso da citometria de fluxo como instrumento eficaz na avaliação da produção de espécies reativas de oxigênio por células do líquido sinovial ativadas pelos estímulos de LPS e PMA, tanto quantitativamente como qualitativamente. / Joint disease in horses, specifically osteoarthritis, is one of the most prevalent and debilitating illnesses affecting equine industry and for this reason continued research and improvements in therapeutics are needed. Osteoarthritis is a degenerative disease that can be triggered by a number of factors and where ultimately all articular tissues are affected. The hallmark of osteoarthritis is the degeneration of the articular cartilage matrix, where the most relevant and expressive events take place. In the development of osteoarthritis there is disruption in extracellular matrix homeostasis with an overall balance toward cartilage metabolism. Homeostasis of the articular environment relies on balance between anabolic and catabolic events and results in ability of cartilage to respond to molecular or mechanical cues. This apparently antagonic processes are orquestrated by soluble protein mediators, for example the anabolic insulin-like growth factor-I (IGF-I), and, on the other side, by inflammatory cytokines, which in turn, are implicated in degradative processes of articular cartilage, characteristic of osteoarthritis. They deplete cartilage matrix from collagen and proteoglycans and the classical example of such a cytokine is interleukin-1. Interleukin-1 has a central role in the physiopathologic processes of osteoarthritis and has been implicated in the genesis of a number of catabolic events when acting on chondrocytes and synoviocytes. Examples are gene induction for metalloproteinases and agrecanases production, as well as production of other inflammatory mediators like ciclooxygenase, prostaglandin E2 and oxygen-derived reactive species. Its biological effects are observed after interaction with two different but specific types of receptors and are modulated by the occurrence of a natural antagonist, the interleukin-1 receptor antagonist protein (IRAP). In the present study the anti-inflammatory effects of this antagonist protein were evaluated in synovial fluid using cytometric flow techniques. It was observed that: 1- addition of IRAP to synovial fluid cells stimulated in vitro by LPS and PMA reduced the production of oxygen-derived reactive species; 2- plasma, used as a control, exhibited similar effects on activated synovial cells when compared to IRAP in vitro 3- the anti-inflammatory effect is due, in its majority, to the variation in intensity of oxygen-derived reactive species, more than on fluctuations on the percentage of synovial fluid cells actively engaged in its generation in vitro. These results support the therapeutic aplicability of IRAP® for its anti-inflammatory effect observed on synovial fluid cells evaluated with flow cytometric techniques. They also corroborate to the usefulness of cytometric flow techniques in equine synovial fluid cells; they are an invaluable tool to evaluate quantitative and qualitatively the production of oxygen-derived reactive species mediated by their activation with PMA and LPS.

O presente estudo se propôs a explorar o uso de um teste de preconceito implícito (IRAP) e de uma medida de grupo (entrevista sociométrica) para a investigação do preconceito étnico em crianças em contexto escolar. Foram investigados possíveis efeitos de duas intervenções para redução de preconceito que enfatizam características de práticas culturais comuns: descrever contingências de reforçamento envolvendo respostas de tolerância e descrever respostas de punição envolvendo respostas de intolerância. Os participantes foram 65 crianças brasileiras e bolivianas de três turmas do último ano do ensino fundamental, faixa etária entre 10 e 11 anos, e três professoras das turmas correspondentes. A porcentagem de crianças bolivianas nos grupos Controle, Intervenção A e Intervenção B foram, respectivamente, 47,1%, 34,8% e 44%. Foram aplicados o IRAP e a entrevista sociométrica antes e depois das intervenções. Nos resultados, não foram observados efeitos das intervenções, detectáveis com um intervalo de confiança de 95%, nem no IRAP e nem nos dados derivados da entrevista sociométrica. A entrevista sociométrica se mostrou útil para investigar preconceito étnico nas turmas a partir de uma análise das proporções real e esperada de nomeações de aceitação e rejeição de acordo com a nacionalidade, mas não a partir das categorias de status sociométrico. Esse resultado é provavelmente devido à alta porcentagem de estrangeiros nas turmas, equilibrando as nomeações. Uma grande porcentagem dos participantes não conseguiu atingir o critério de porcentagem de acerto (80%) do IRAP nos blocos de prática e outros não conseguiram manter esse critério durante o teste, sugerindo que o critério de 70% empregado em outros estudos do IRAP com crianças é mais adequado. O principal resultado deste estudo demonstrou um índice de preconceito nas salas que já era de conhecimento de algumas das professoras, ainda que não de todas. No entanto, a investigação e quantificação de fenômenos conhecidos é o que permite avaliar os efeitos de intervenções sobre eles, facilitando a realização de novas pesquisas que poderão embasar no futuro práticas e políticas públicas mais eficazes / Prejudice research is an active field in psychology which fosters many studies on interventions aimed at prejudice reduction. Data collected in these studies are usually individual measures, such as questionnaires and implicit prejudice tests. Data is usually collected in laboratories or other non-realistic settings. The present study explored the combination of an individual implicit prejudice measure (IRAP) with a social measure (sociometric interview) to investigate ethnic prejudice in children at school. The effects of two prejudice reduction interventions were investigated, both of which replicate characteristics of common practices: describing reinforcement contingencies of tolerance responses and describing punishment contingencies of intolerance/prejudice responses. Participants were 65 brazilian and bolivian children aged 10 to 11 years old, and their teachers. Control Group, Intervention A Group and Intervention B Group had, respectively, 47,1%, 34,8% and 44% bolivian students. IRAP and the sociometric interview were applied before and after the interventions. No effects of the interventions were observed in either individual or social measures. The sociometric interview proved to be useful to investigate prejudice among the students when expected and actual sociometric nominations ratios were compared, but not when sociometric statuses were compared. This is so probably due to the high percentage of bolivians in the groups, as they balance out the nominations. More than half of the participants were not able to fulfill the practice criterion of accuracy (80%) of the IRAP; others were not able to maintain this criterion across the test blocks. This suggests the 70% accuracy criterion to be best suitable for children. The main result here presented regards the assessment of the amount of prejudice and segregation amongst students, which was already known to some of the teachers. However, quantifying known phenomenons allows the evaluation of the effects interventions have on them, making it possible to further research on the topic and to develop better practices and public policies

A doença articular, especificamente a osteoartrite é uma das enfermidades mais prevalentes e mais debilitantes que acomete os cavalos, tendo um grande impacto econômico na indústria eqüina. Assim sendo, a investigação contínua e avanços na área terapêutica são de fundamental importância. A osteoartrite é uma doença degenerativa que pode ser deflagrada por uma série de fatores e onde, ultimamente, todos os tecidos articulares encontram-se comprometidos. Não obstante, é na degradação da matriz extracelular da cartilagem articular que ocorrem os eventos de maior expressão e repercussão. Na gênese da degradação da matriz extracelular encontra-se um desequilíbrio entre os processos anabólicos e catabólicos responsáveis pela homeostase normal da cartilagem articular e pela adaptação deste tecido às forças que sobre ele incidem. Estes processos são orquestrados por proteínas anabólicas, como, por exemplo o fator de crescimento tipo insulina 1 (IGF-l), e por citocinas inflamatórias que, de forma contrária, são responsáveis pela depleção de colágeno e de proteoglicanas da matriz, representando o grupo de proteínas catabólicas, cujo exemplo clássico é a interleucina-1. A interleucina-1 tem papel central nos processos fisiopatológicos da osteoartrite por desencadear vários eventos catabólicos nos sinoviócitos e condrócitos, incluindo a indução de gens de metaloproteinases e agrecanases e de outros mediadores inflamatórios como a cicloxigenase, a prostaglandina E2 e as espécies reativas do oxigênio. Seus efeitos biológicos se verificam após a ligação com dois tipos de receptores específicos e são modulados pela ocorrência natural de uma proteína antagonista destes receptores. O presente estudo procurou observar os efeitos antiinflamatórios desta proteína antagonista do receptor (IRAP) no líquido sinovial de equino através do emprego da técnica de citometria de fluxo. Nos ensaios observou-se que: 1-a adição de IRAP às células de líquido sinovial estimuladas in vitro por LPS e PMA reduziu a liberação de espécies reativas de oxigênio produzidas por elas; 2 - o plasma, quando utilizado como controle, exibiu efeitos semelhantes aos do IRAP sobre as células de líquido sinovial ativadas in vitro; 3- o efeito antiinflamatório deve-se mais à variação na intensidade de produção de espécies reativas do oxigênio do que à flutuação no percentil de células do líquido sinovial engajadas em sua geração, in vitro. Estes resultados suportam a aplicabilidade terapêutica do IRAP® pelo efeito antiinflamatório verificado sobre as células do liquido sinovial avaliadas por citometria de fluxo. Eles corroboram, ainda, para o uso da citometria de fluxo como instrumento eficaz na avaliação da produção de espécies reativas de oxigênio por células do líquido sinovial ativadas pelos estímulos de LPS e PMA, tanto quantitativamente como qualitativamente. / Joint disease in horses, specifically osteoarthritis, is one of the most prevalent and debilitating illnesses affecting equine industry and for this reason continued research and improvements in therapeutics are needed. Osteoarthritis is a degenerative disease that can be triggered by a number of factors and where ultimately all articular tissues are affected. The hallmark of osteoarthritis is the degeneration of the articular cartilage matrix, where the most relevant and expressive events take place. In the development of osteoarthritis there is disruption in extracellular matrix homeostasis with an overall balance toward cartilage metabolism. Homeostasis of the articular environment relies on balance between anabolic and catabolic events and results in ability of cartilage to respond to molecular or mechanical cues. This apparently antagonic processes are orquestrated by soluble protein mediators, for example the anabolic insulin-like growth factor-I (IGF-I), and, on the other side, by inflammatory cytokines, which in turn, are implicated in degradative processes of articular cartilage, characteristic of osteoarthritis. They deplete cartilage matrix from collagen and proteoglycans and the classical example of such a cytokine is interleukin-1. Interleukin-1 has a central role in the physiopathologic processes of osteoarthritis and has been implicated in the genesis of a number of catabolic events when acting on chondrocytes and synoviocytes. Examples are gene induction for metalloproteinases and agrecanases production, as well as production of other inflammatory mediators like ciclooxygenase, prostaglandin E2 and oxygen-derived reactive species. Its biological effects are observed after interaction with two different but specific types of receptors and are modulated by the occurrence of a natural antagonist, the interleukin-1 receptor antagonist protein (IRAP). In the present study the anti-inflammatory effects of this antagonist protein were evaluated in synovial fluid using cytometric flow techniques. It was observed that: 1- addition of IRAP to synovial fluid cells stimulated in vitro by LPS and PMA reduced the production of oxygen-derived reactive species; 2- plasma, used as a control, exhibited similar effects on activated synovial cells when compared to IRAP in vitro 3- the anti-inflammatory effect is due, in its majority, to the variation in intensity of oxygen-derived reactive species, more than on fluctuations on the percentage of synovial fluid cells actively engaged in its generation in vitro. These results support the therapeutic aplicability of IRAP® for its anti-inflammatory effect observed on synovial fluid cells evaluated with flow cytometric techniques. They also corroborate to the usefulness of cytometric flow techniques in equine synovial fluid cells; they are an invaluable tool to evaluate quantitative and qualitatively the production of oxygen-derived reactive species mediated by their activation with PMA and LPS.

O presente estudo se propôs a explorar o uso de um teste de preconceito implícito (IRAP) e de uma medida de grupo (entrevista sociométrica) para a investigação do preconceito étnico em crianças em contexto escolar. Foram investigados possíveis efeitos de duas intervenções para redução de preconceito que enfatizam características de práticas culturais comuns: descrever contingências de reforçamento envolvendo respostas de tolerância e descrever respostas de punição envolvendo respostas de intolerância. Os participantes foram 65 crianças brasileiras e bolivianas de três turmas do último ano do ensino fundamental, faixa etária entre 10 e 11 anos, e três professoras das turmas correspondentes. A porcentagem de crianças bolivianas nos grupos Controle, Intervenção A e Intervenção B foram, respectivamente, 47,1%, 34,8% e 44%. Foram aplicados o IRAP e a entrevista sociométrica antes e depois das intervenções. Nos resultados, não foram observados efeitos das intervenções, detectáveis com um intervalo de confiança de 95%, nem no IRAP e nem nos dados derivados da entrevista sociométrica. A entrevista sociométrica se mostrou útil para investigar preconceito étnico nas turmas a partir de uma análise das proporções real e esperada de nomeações de aceitação e rejeição de acordo com a nacionalidade, mas não a partir das categorias de status sociométrico. Esse resultado é provavelmente devido à alta porcentagem de estrangeiros nas turmas, equilibrando as nomeações. Uma grande porcentagem dos participantes não conseguiu atingir o critério de porcentagem de acerto (80%) do IRAP nos blocos de prática e outros não conseguiram manter esse critério durante o teste, sugerindo que o critério de 70% empregado em outros estudos do IRAP com crianças é mais adequado. O principal resultado deste estudo demonstrou um índice de preconceito nas salas que já era de conhecimento de algumas das professoras, ainda que não de todas. No entanto, a investigação e quantificação de fenômenos conhecidos é o que permite avaliar os efeitos de intervenções sobre eles, facilitando a realização de novas pesquisas que poderão embasar no futuro práticas e políticas públicas mais eficazes / Prejudice research is an active field in psychology which fosters many studies on interventions aimed at prejudice reduction. Data collected in these studies are usually individual measures, such as questionnaires and implicit prejudice tests. Data is usually collected in laboratories or other non-realistic settings. The present study explored the combination of an individual implicit prejudice measure (IRAP) with a social measure (sociometric interview) to investigate ethnic prejudice in children at school. The effects of two prejudice reduction interventions were investigated, both of which replicate characteristics of common practices: describing reinforcement contingencies of tolerance responses and describing punishment contingencies of intolerance/prejudice responses. Participants were 65 brazilian and bolivian children aged 10 to 11 years old, and their teachers. Control Group, Intervention A Group and Intervention B Group had, respectively, 47,1%, 34,8% and 44% bolivian students. IRAP and the sociometric interview were applied before and after the interventions. No effects of the interventions were observed in either individual or social measures. The sociometric interview proved to be useful to investigate prejudice among the students when expected and actual sociometric nominations ratios were compared, but not when sociometric statuses were compared. This is so probably due to the high percentage of bolivians in the groups, as they balance out the nominations. More than half of the participants were not able to fulfill the practice criterion of accuracy (80%) of the IRAP; others were not able to maintain this criterion across the test blocks. This suggests the 70% accuracy criterion to be best suitable for children. The main result here presented regards the assessment of the amount of prejudice and segregation amongst students, which was already known to some of the teachers. However, quantifying known phenomenons allows the evaluation of the effects interventions have on them, making it possible to further research on the topic and to develop better practices and public policies

The increased understanding of underlying neurobiological processes and their connections to cognitive performance has opened new doors for novel therapeutic strategies that aim to prevent, and even reverse the effects of memory disorders, neurodegenerative diseases and other cognitive impairments. One of the new and exciting drug targets that has emerged as a result of this research is insulin-regulated aminopeptidase (IRAP). While the research is still in its early stages, inhibition of IRAP have promising therapeutic potential and several small molecule and peptidomimetic candidates that act as inhibitors of IRAP have been synthesized. Analysis of in vivo performed novel object recognition tests, in vitro cell viability and morphology assays were conducted in this study to further investigate the cognitive effects and other effects of an IRAP-inhibitor called HA08. Recorded novel object recognition test previously performed on rats were scored and analysed with statistical software. Primary cortical and hippocampal cells harvested from rat fetuses were treated with increasing concentrations of HA08 and oxytocin. The cell viability assays consisted of LDH assays to analyse HA08’s effect on the cells membrane integrity and MTT assays to analyse its effect on mitochondrial function. Immunocytochemistry was used to assess the difference in neurite length in cortical cells and the number of dendritic spines in hippocampal cells. No increases in recognition were found in HA08 treated rats. HA08 did not seem to affect the membrane integrity at concentrations used. Further research is needed to improve the accuracy of the results and to fully unlock the potential of IRAP-inhibitor HA08.